Intra Vitreal

Anti-VEGF
Ima Yustiarini
Ady Dwi Prakosa, Sauli A. Widjaja, Muh Firmansjah, Wimbo Sasono,
Moestidjab, Gatut Suhendro

Vitreoretina Division, Department of Ophthalmology

Faculty of Medicine Universitas Airlangga / Dr. Soetomo General Academic Hospital Surabaya
2019
 Intra Vitreal Injection(IVI)
• First introduced in 1911 → administering air inside the eye
• After 1945 → pathway for dispensing different drugs, in the treatmen
t of endophthalmitis, retinal detachments.
• Recent years → the most common intraocular procedure worldwide
with increasing numbers every year

2007 2013
• Less than • More • 5.9
5000 • 800.000 than 1 • Over 4 million
IVI/year IVI million million IVI (USA)
1997-2001 2009 IVI (USA) 2016
IVI (USA)

Anti-VEGF
 VEGF
• Vascular Endothelial Growth Factor, responsible for growth of blood
vessels
• Maintaining blood flow to RPE and Photoreceptors
• Responsible for many retinal diseases
1. Stimulates Angiogenesis
2. Inducer of vascular permeability causing retinal swelling
3. Pro-inflammatory
• Produced by different stimuli in
• RPE Cells
• Neurons
• Glial Cells
• Endothelial Cells
• Ganglion Cell, Muller Cells, and smooth muscle cells
 Initiating stimuli for VEGF release

Hypoxia

Oxidative stress to
Retina and RPE

Accumulation of Pathologic VEGF-A secreted

Lipid Metabolic by by RPE
product

Alteration in Bruch
membrane

Drusen
Anti-VEGF agents
 Bevacizumab (Avastin)

• First approval 2004, for metastatic colon cancer

• Off label use in ophthalmology (not yet approved by FDA)
• Dosage : 1,25 mg in adult, half dose in babies
• Adverse Effect :
• CVS : Hypertension, Tromboembolism
• CNS : Headache, dizziness, sensory neuropathy
• GIT : Abdominal pain, vomitting
• Renal – proteinuria >3,5 mg
 Ranibizumab (Lucentis,Patizra)

• Approved for nAMD in 2006 (US)

• FDA approval for DME in 2015
• Dosage : 0,5 mg
• Risk of CVS but safe in renal impairment
 Aflibercept (Eylea)
• FDA approval in December 2011
• Dosage : 2 mg
• Aflibercept is a fusion protein for intravitreal injection that ‘traps’ VEGF-
A and PGF molecules
Incorporates domains from two VEGFR-1
VEGF receptors for tight binding on domain VEGF dimer
VEGFR-2
both sides of VEGF and PGF,
domain
preventing interactions with other
molecules2

Aflibercept binds more

Fc fragment tightly to VEGF than the
of IgG native VEGF receptors2

Aflibercept molecule
Aflibercept–VEGF complex

Fc, fragment, crystallizable; IgG, immunoglobulin G; PGF, placental growth factor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.
1. Papadopoulos N et al. Angiogenesis 2012; 15 (2): 171–185. 2 Bayer Pharma AG. EYLEA – summary of product characteristics; August 2016.
 Euretina
IVI
Consensus
2018
 Common Anti VEGF Use

Retinal Vein
Occlusion
Wet AMD Myopic CNV

Adjuvant Tx
Diabetic for Surgery
Macular
Edema ROP
 Contraindication

• Major systemic event in past 3 months

• Stroke
• Cardiac arrest
• Uncontrolled hypertension
• Fibrovascular proliferation threatening macula
• Active ocular and periocular inflammation
• Known hypersensitivity to anti-VEGF agent
 Side Effects
• Subconjuctival Hemorrhage
• Vitreous Hemorrhage
• Increasing in Intra Ocular Pressure
• Intraocular inflammation 1,4-2,9%
• Infectious Endophthalmitis, reported in 0,09 – 1,6 % of the cases in
multicenter trials
• Other Complication (Retinal Vascular Occlusion, Corneal Abrasions,
Cataract progression, RPE tear, Retinal tear or detachment)
 Neovascular AMD (Anti VEGF Management)…....

❑ RANIBIZUMAB

ANCHOR & MARINA :

• 95% visual stabilized in occult CNV (compared sham)
→ MARINA study
• 40% vision improvement 15 letters or more in Classic CNV
compared to PDT) → ANCHOR study
• Treat & Extend
 Neovascular AMD (Management)…....

• PRONTO, SAILOR, HORISON & SUSTAIN

3 monthly injection & followed as needed treatment, based on
clinical & OCT guided criteria. The result is comparable with
previous study Marina & Anchor

• HARBOUR
No difference in result between higher dose (2.0 mg) ranibizumab with
standard dose (0,5 mg)
 Neovascular AMD (Anti VEGF Management)…....

❑ AFLIBERCEPT

• Combined of ligand binding protein element with Immunoglobulin G

• VIEW 1 & 2 : comparison between Aflibercept monthly / 2 months
injection to Ranibizumab injection monthly. The result is not inferior
• The result after 3 months injection, Aflibercept 2 months injection
has the same efficacy with Ranibizumab monthly injection
 Neovascular AMD (Anti VEGF Management)…....

❑ BEVACIZUMAB
• CATT study :
– At first years, both drugs had an equivalent effect on visual acuit
y
– After two years, mean gain in visual acuity was similar for both
drugs (Ranibizumab-Bevacizumab )
• Mean visual gain was greater for monthly treatment than for
as needed.

• MANTA study :
– Compared as needed protocol Bevacizumab & Ranibizumab,
found similar results in both group.
 Therapeutic Response
• Anatomical Criteria
• <50% reduction in CMT after 3 monthly injection → inadequate

• Functional Criteria
• Failed to improve to 20/40 after 3 monthly injection → inadequate
 Treatment Regimens
PROACTIVE
FIXED DOSING
Regular injections not dependent VA o
r anatomic status
TREAT-AND-EXTEND
Treatment interval :
VA, anatomic response or
duration of VEGF suppression
Inject at scheduled visit
regardless of VA and/or
anatomic status
REACTIVE
PRN
Monitor regularly (monthly) and treat
according to VA and/or anatomic
criteria
TREAT TO TARGET
Regular injections until stable disease
VA , anatomic criteria
Monitor response and re-treat
VA, anatomic criteria
PRN, pro re nata (as needed); VA, visual acuity; VEGF, vascular endothelial growth
factor.
 PRN example case
1st Injection anti VEGF 4 weeks interval 4 weeks interval
Injection anti VEGF Injection anti VEGF

4 weeks interval 4 weeks interval 4 weeks interval

No Injection anti VEGF No Injection anti VEGF recurrence
Injection anti VEGF

4 weeks interval – dry 4 weeks interval 4 weeks interval

No Injection anti VEGF No Injection anti VEGF No Injection anti VEGF

Key : Monitoring every 4 weeks and only inject if recurrence (Reactive)

Gupta OP. 2011. Retina Today. April
Treat to Extend Treatment example case
1st Injection anti VEGF 4 weeks interval 4 weeks interval – dry
Injection anti VEGF Injection anti VEGF

6 weeks interval 8 weeks interval 10 weeks interval – recurrence

Injection anti VEGF Injection anti VEGF Injection anti VEGF

8 weeks interval – dry 10 weeks interval 12 weeks interval

Injection anti VEGF Injection anti VEGF Injection anti VEGF

Key : Extend Monitoring based on visual and anatomic result and inject every time of
monitoring visit (Proactive)
Gupta OP. 2011. Retina Today. April
 Therapeutic Failure
• Tachyphylaxis
• Phenomena causing reduced drug efficacy by repeated administration
→ discontinuation or switching

• Tolerance
• Slow loss of efficacy overtime
→ restored by increasing dosage or shortening time interval

• Refractory
• Persistent intra/subretinal fluid for 4-6 months

• Increased intra/subretinal fluid after 2 or more injection

• Recurrency
• Well response but frequent IVI injection to maintain dry macula
 Anti VEGF Treatment Regimen
Under Treatment Over Treatment

Patient burden
Clinic burden
Costs
Heink de Groot HD, et al., Mechanisms of Ocular Angiogenesis and Its Molecular Mediators., 2010
 Anti VEGF Treatment Regimen
Under Treatment Over Treatment

Submacular fibrosis & atrophy

Thinning retina & choroid
Systemic effect
Heink de Groot HD, et al., Mechanisms of Ocular Angiogenesis and Its Molecular Mediators., 2010
 Therapeutic Response

• Patient burden must also be considered

▪ A therapeutic response is Favorable if the number of injections can be reduced to
have better morphological changes

▪ A therapeutic response is Not Favorable if a lot of injections are required to observe

a few morphological changes